Generally, insulin is a hormone secreted by the pancreas of the human body, which regulates blood glucose levels, and plays a role in maintaining normal blood glucose levels while carrying surplus glucose in the blood to cells to provide energy for cells. In diabetic patients, however, insulin does not function properly due to lack of insulin, resistance to insulin, and loss of beta-cell function, and thus glucose in the blood cannot be utilized as an energy source and the blood glucose level is elevated, leading to hyperglycemia. Eventually, urinary excretion occurs, contributing to development of various complications. Therefore, insulin therapy is essential for patients with abnormal insulin secretion (Type I) or insulin resistance (Type II), and blood glucose levels can be normally regulated by insulin administration. However, like other protein and peptide hormones, insulin has a very short in-vivo half-life, and thus has a disadvantage of repeated administration. Such frequent administration causes severe pain and discomfort for the patients. For this reason, in order to improve quality of life by increasing an in-vivo half-life of the protein and reducing the administration frequency, many studies on protein formulation and chemical conjugation (fatty acid conjugate, polyethylene polymer conjugate) have been conducted. Commercially available long-acting insulin includes insulin glargine manufactured by Sanofi Aventis (lantus, lasting for about 20 hours to 22 hours), and insulin detemir (levemir, lasting for about 18 hours to 22 hours) and tresiba (degludec, lasting for about 40 hours) manufactured by Novo Nordisk. These long-acting insulin formulations produce no peak in the blood insulin concentration, and thus they are suitable as basal insulin. However, because these formulations do not have a sufficiently long half-life, the disadvantage of one or two injections per day still remains. Accordingly, there is a limitation in achieving the intended goal that administration frequency is remarkably reduced to improve convenience of diabetic patients in need of long-term administration.
Authier F et al. (Biochem J. 1998 Jun. 1; 332 (Pt 2): 421-30), Duckworth W C et al. (Endocr Rev. 1998 October; 19(5): 608-24) and Valera Mora M E et al. (J Am Coll Nutr. 2003 December; 22(6): 487-93), etc., have reported in-vivo insulin clearance processes. According to the reports, 50% or more of insulin is removed in the kidney and the rest is removed via a receptor mediated clearance (RMC) process in target sites such as muscle, fat, liver, etc.
In this regard, Lin S et al. (J Pharmacol Exp Ther, 1998, 286(2): 959-66), Brange J et al. (Diabetes Care. 1990 September; 13(9): 923-54), and Ribel U et al. (Diabetes, 1990, 39: 1033-9), etc., have reported that in-vitro activity is reduced to avoid RMC of insulin, thereby increasing the insulin level in the blood.
Under these circumstances, the present inventors have made many efforts to increase the blood half-life of insulin. As a result, they have discovered an insulin analog that has reduced insulin receptor binding affinity, and also confirmed that a formulation containing the same, which is capable of increasing the half-life, bioavailability, and maintaining sustained activity of insulin, can also increase the blood half-life of insulin, thereby completing the present invention.